In some patients with neuropathy and plasma cell dyscrasia there are IgM M-proteins that react with nerve components and that may cause the neuropathy. In approximately half the patients the neuropathy is demyelinating and the M-proteins bind to myelin. In the other patients there is primary axonal degeneration and the M-proteins bind to nerve axons or to endoneurium. The M-proteins that bind to myelin were initially found to bind to the myelin associated glycoprotein (MAG) but recent evidence suggest that the M-proteins bind to a carbohydrate determinant that is shared by central and peripheral MAG and by other glycoproteins and gangliosides in peripheral nerve. There is also evidence that secretion of the M-proteins may be regulated by T-lymphocytes. The aims of the proposed project are to: 1) characterize the carbohydrate determinant to which the anti-MAG M-proteins bind in patients with demyelinating neuropathies; 2) identify and characterize the nerve antigens to which the M-proteins bind in patients with axonal neuropathies; 3) determine if the identified nerve antigens are also immunologically involved in other patients with neuropathies of unknown etiology; 4) determine whether the anti-MAG M-proteins from patients with demyelinating neuropathy or any of the M-proteins from patients with axonal neuropathies share idiotypic or heavy chain variable region (Vh) determinants; and 5) elucidate the T and B cell interactions regulating production of the M-proteins in vitro and determine if there are idiotype specific or antigen specific T-cells present which may regulate the M-protein secreting B-cells. The project is of interest and important for a number of reasons. It would help diagnose and classify patients with peripheral neuropathies and identify those who may benefit from therapeutic intervention; characterization of the target antigens will allow the development of analogues which could be used to block or remove circulating M-proteins; demonstration of shared Vh determinants between M-proteins from different patients would suggest that there may be an abnormality linked to the expression of the Vh regions, and elucidation of the T and B cell interactions regulating secretion of the M-proteins may lead to the development of more specific and effective therapy.